Use of serotonergic compound for a method of treatment of hot flushes in post-menopausal women.
The invention relates to the use of a serotonergic compound for the treatment of hot flushes.
The most well-known complaints of the (post)-menopausal syndrome are due to changes in temperature regulation, causing sudden crises of feelings of excessive body heat (hot flushes). These symptoms are highly disturbing for a large proportion of menopausal women, leading to therapy requests to the medical profession. Usually, replacement of estrogens is selected as remedy. Less commonly and more recently explored is the selection of non-hormonal compounds as medicine for treating hot flushes. For example, the use of serotonergic uptake inhibitors and serotonin (=5-hydroxy-tryptophan=5-HT) antagonists for the treatment of hot flushes is discussed in Berendsen, Maturitas Vol 36, pp 155-164, 2000. Some beneficial effects of 5-HT2A antagonists and serotonin uptake inhibitors were reported. The beneficial effect of the serotonin reuptake inhibitors sertraline and paroxetine were described in Plouffe et al., Delaware Medical Journal 69: pp 481-482, 1997, Roth and Scher, Psycho-Oncology 7, pp 129-132, 1998, and Stearns et al., Annals of Oncology 11, pp 17-22, 2000.
It has now been found that an agonist for 5-HT2C receptors in an organism can be used for a method of treatment of hot flushes.
Unexpectedly, these 5-HT2C-agonists produce better results than SSRI""s against hot flushes in view of the extent to which side effects are compensated for by efficacy.
Thus, the invention provides for a method of treatment of hot flushes with a 5-HT2C receptor agonist. In particular, a selective 5-HT2C receptor agonist is preferred. A selective 5-HT2C receptor agonist in the context of the description of this invention means a 5-HT2C receptor agonist which is more active as agonist on 5-HT2C receptors than on other 5-HT receptor subtypes, such as 5-HT1A, 5-HT2A and/or 5-HT3 receptors. The selective 5-HT2C receptor agonist should preferably be such that it is at least 5 times more active on 5-HT2C receptors than on the other serotonin receptors. The 5-HT agonists described in EP 370 560 are particularly suitable for the use of this invention. Specifically 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and its pharmaceutically acceptable acid addition salts have the most desirable properties out of this group for the use of this invention. More preferred is the use of a 5-HT2C agonist being at least 10 times more active on 5-HT2C receptors relative to 5-HT2A receptors. Most preferred is the use of the azetidines or pyrrolidine compounds disclosed in EP863136 for use in the treatment of hot flushes, and in particular the compound (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine or its pharmaceutically acceptable acid addition salts described in that disclosure.
Since the treatment of the present invention is not based on hormone replacement these treatment agents are preferably used in those circumstances were treatment with a hormone or a hormone receptor agonist bears higher risks. Therefore, an aspect of this invention is that it makes a treatment available for hot flushes in patients at risk for hormone dependent tumour growth. Such patients are the group of patients with ovariectomy in view of estrogen dependent tumour growth. Another aspect of the invention is that it makes a treatment available for hot flushes in patients with adverse feminizing responses to estrogens. In particular, male patients functionally or pharmacologically castrated for the purpose of removing endogenous hormones can be treated for hot flushes with 5-HT2C-agonists. Hot flushes not only occur as complaint during menopause, but also in certain women during specific points in time of the mensual cycle, for example before and during the days of menstruation. It is an aspect of this invention that hot flushes in those circumstances can be very well non-hormonally treated with a 5-HT2C agonist.
The terms used in this description have the meaning according to common understanding of these terms. The accepted use of the terminology to indicate serotonin receptor subtypes is for example used in Barnes and Sharp, Neuropharmacology 38, pp 1083-1152, 1999. A serotonergic compound is a compound which directly or indirectly, for example as agonist or as serotonin reuptake inhibitor activates serotonin receptors in an organism. An agonist for a receptor is a compound which produces an effect caused by conformational changes of the receptor by direct binding to the receptor. For the 5-HT2C receptor the agonist mimicks at least partially the effect of serotonin. Thus, a partial agonist is explicitly included within the scope of this invention. It is in many circumstances beneficial to use a partial agonist rather than a full agonist. The former might be less efficacious but may have less risk for full-blown adverse overdose effects.
Determination of selectivity of a receptor agonist can be done by methods well known in the art. The basic technique is with binding experiments in which the compound is tested for binding affinity to the subtypes of receptors. Alternatively, selectivity can be determined with in vitro expression systems in which a biochemical parameter, such as cyclic adenosine monophosphate or phosphoinositol production or inhibition is used to determine receptor activation by an agonist. In vivo methods can also be used when selective models for testing receptor stimulation are available. Some differences in the selectivity results obtained with these methods can occur. Usually, and under the condition that the test is accepted as reliable, the in vivo selectivity is the preferred indicator for determination of selectivity of a compound over in vitro methods. Results with in vitro expression of receptor activity are in turn more preferred for determination of the selectivity than binding experiments. For a suitable collection of techniques to determine the properties of a 5-HT2C agonist reference is made to Martin et al., 5-HT2C receptor agonists: Pharmacological characteristics and therapeutic potential. J. Pharmacol and Experimental Therapeutics 286: 913-924, 1998.
The present invention further includes the use of a 5-HT2C-agonist for the manufacture of a medicament for the treatment of hot flushes.
Suitable acid addition salts include hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation. A preferred salt is the hydrochloric acid salt.
The amount of a 5-HT2C agonist, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration and the age and other conditions of the recipient.
A suitable daily dose for any of the two compounds chemically named above will be in the range of 5 to 140 mg of the base per person per day, preferably in the range of 20 to 70 mg of the base per recipient per day. In the case of tolerance development, treatments can be further optimalised by increasing the dose up to 5 times in the course of a chronic treatment in humans. The desired dose may be presented as one, two, three or more sub-doses administered at appropriate intervals throughout the day.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation for use in the treatment of hot flushes comprising a 5-HT2C-agonist, together with a pharmaceutically acceptable carrier thereof and optionally other therapeutic agents. The carrier must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof. The invention further includes a pharmaceutical formulation, as hereinbefore described, in combination with packaging material suitable for the pharmaceutical formulation, said packaging material including instructions for the use of the pharmaceutical formulation in the treatment of hot flush.
Formulations include those suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and epidural) administration. The formulations may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al.,Remington""s Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see especially Part 8: Pharmaceutical Preparations and their Manufacture). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. Such accessory ingredients include those conventional in the art, such as, fillers, binders, diluents, disintegrants, lubricants, colorants, flavoring agents and wetting agents.
Formulations suitable for oral administration may be presented as discrete units such as tablets or capsules each containing a predetermined amount of active ingredient; as a powder or granulates; as a solution or suspension. The active ingredient may also be presented as a bolus or paste, or may be contained within liposomes or microparticles.
Formulations for rectal administration may be presented as a suppository or enema.
For parenteral administration, suitable formulations include aqueous and non-aqueous sterile injection. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed vials and ampoules, and may be stored in a freeze dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, water prior to use.
Formulations suitable for administration by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurised aerosols, nebulisers or insufflators.
Formulations may, for example, be presented in a suitable sustained release form, for example, in a device such as the Minipump(trademark).
The compounds according to the present invention are non-toxic.
The the compounds 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine and (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine, and their pharmaceutically acceptable acid addition salts may be prepared by any method known in the art for the preparation of a compound of similar structure. Typically the compound 1-[6-chloro-5-(trifluoromethyl)-2-pyridinyl]-piperazine can be prepared by the methods described in EP 370 560, the contents of which are incorporated herein by reference, whereas the compound (S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy-pyrrolidine and its pharmaceutically acceptable acid addition salts can be prepared by the methods described in EP863136, the contents of which are incorporated herein by reference.
The following example is for illustration and should not be considered to be limiting in anyway: